Reproductive System

GnRH from the hypothalamus is released in pulses every ≈60–120 min; pulsatility is essential (continuous GnRH desensitises the pituitary). Fast pulses favour LH, slow pulses favour FSH. In the testis, LH stimulates Leydig cells to make testosterone; FSH and very high intratesticular testosterone act on Sertoli cells to support spermatogenesis, and Sertoli cells secrete inhibin B, which selectively suppresses FSH. Testosterone (partly after aromatisation to estradiol) inhibits GnRH and LH. In the ovary, the two-cell, two-gonadotropin system operates: LH drives theca cells to make androgens, FSH drives granulosa-cell aromatase to convert them to estradiol. Estradiol and inhibin normally exert negative feedback, but a sustained high estradiol level from the dominant follicle switches the hypothalamus and pituitary to positive feedback, producing the LH surge that causes ovulation. Kisspeptin neurons in the arcuate nucleus act as the gatekeepers of GnRH secretion, integrating nutritional (leptin), stress and steroid signals.

Spermatogenesis takes place in the seminiferous epithelium, moving from the basement membrane towards the lumen. (1) Spermatocytogenesis: stem spermatogonia (type A dark = reserve, type A pale = renewing) divide by mitosis; type B spermatogonia differentiate into primary spermatocytes (2n, 4C), which cross the blood–testis barrier. (2) Meiosis: meiosis I (with a long prophase of ≈3 weeks) gives two secondary spermatocytes (n, 2C), which rapidly complete meiosis II to give four haploid spermatids. Daughter cells remain joined by cytoplasmic bridges and develop synchronously. (3) Spermiogenesis (no division): the Golgi forms the acrosome, the nucleus condenses as histones are replaced by protamines, the distal centriole grows the flagellum, mitochondria wrap the midpiece, and excess cytoplasm is shed as a residual body, phagocytosed by Sertoli cells. (4) Spermiation releases the spermatozoa into the lumen. The cycle takes ≈64–74 days, so any insult (fever, drugs, chemotherapy) shows up in semen analysis about 3 months later. Spermatozoa leaving the testis are immotile and acquire progressive motility in the epididymis, and the ability to fertilise only after capacitation in the female tract.

Oogenesis begins before birth. Primordial germ cells reach the ovary by week 6; oogonia multiply to a peak of ≈6–7 million at about 20 weeks, enter meiosis I and become primary oocytes, which arrest in prophase I (diplotene/dictyate stage) inside primordial follicles. Most undergo atresia, leaving ≈1–2 million at birth. From puberty, each LH surge causes the oocyte of the ovulating follicle to complete meiosis I just before ovulation, producing a secondary oocyte and the first polar body; the secondary oocyte arrests again at metaphase II and completes meiosis II only if fertilised, producing the second polar body. Cytokinesis is unequal, so each primary oocyte gives one large gamete.

Key contrasts: spermatogenesis starts at puberty, is continuous, lifelong and supplied by self-renewing stem cells, and each primary spermatocyte gives four equal spermatids in ≈2–3 months. Oogenesis starts in fetal life, has two arrests lasting up to five decades, draws on a finite, non-renewable pool and gives one oocyte plus polar bodies. The very long prophase I arrest is thought to underlie the rise in meiotic non-disjunction (e.g. trisomy 21) with maternal age.

Day 1 is the first day of menstruation. Follicular / proliferative phase (≈days 1–14, variable length): the fall of luteal estradiol, progesterone and inhibin A lets FSH rise; a cohort of antral follicles grows, one becomes dominant by ≈days 5–7 and its rising estradiol suppresses FSH (the others become atretic) and rebuilds the endometrium from the basal layer (proliferative phase; straight glands; thin, stretchy cervical mucus). Ovulation (≈day 14): estradiol peaks ≈1 day before the LH surge; ovulation follows ≈24–36 h after surge onset. Luteal / secretory phase (fixed ≈14 days): the corpus luteum secretes progesterone (peak ≈day 21) and estradiol; the endometrium becomes secretory (coiled glands, glycogen, oedematous stroma, coiled spiral arteries), cervical mucus thickens and basal body temperature rises ≈0.3–0.5 °C. Without hCG the corpus luteum regresses after ≈10–12 days; falling progesterone causes prostaglandin release, spiral artery constriction, ischaemia and shedding of the functional layer — menstruation (days 1–5).

Hormone curves in summary: FSH — small rise in the early follicular phase, falls mid-follicular, small mid-cycle peak, low in the luteal phase, rises again pre-menstrually. LH — low, then a sharp ≈10-fold surge at mid-cycle. Estradiol — rises steeply in the late follicular phase, dips at ovulation, second smaller plateau mid-luteal. Progesterone — low before ovulation, peaks mid-luteal, falls before menses.

Of the ≈40–300 million sperm ejaculated, only a few hundred reach the ampulla of the uterine tube. Sperm undergo capacitation (hours; removal of cholesterol and glycoproteins from the membrane, hyperactivated motility), penetrate the corona radiata, bind the zona pellucida and undergo the acrosome reaction, digest a path through the zona, and fuse with the oocyte membrane (Izumo1–Juno binding). A sperm factor (PLCζ) triggers Ca²⁺ oscillations that cause the cortical reaction (zona hardening — the block to polyspermy) and the completion of meiosis II. Male and female pronuclei form, replicate their DNA and their chromosomes combine on the first mitotic spindle: the zygote.

Cleavage divisions occur within the zona as the embryo moves down the tube: 2 cells at ≈30 h, a morula of ≈16 cells by day 3–4, entering the uterus about day 4. Fluid accumulates to form the blastocyst (day 4–5) with an inner cell mass (embryoblast) and an outer trophoblast. After hatching from the zona (day 5–6), the blastocyst implants from ≈day 6–7: apposition and adhesion at the embryonic pole, then invasion by the syncytiotrophoblast, which begins to secrete hCG. Implantation is complete by ≈day 10–12; the endometrial stroma responds with the decidual reaction.

Pregnancy lasts ≈40 weeks from the last menstrual period, divided into trimesters (to 13+6 weeks, 14–27+6, 28 weeks to birth). hCG maintains the corpus luteum until the placenta takes over progesterone production at ≈7–9 weeks. Maternal adaptations include a 40–50 % rise in blood volume (with dilutional anaemia), a 30–50 % rise in cardiac output, falling systemic vascular resistance, hypercoagulability, a ≈50 % rise in GFR, increased tidal volume with compensated respiratory alkalosis, and progressive insulin resistance driven by placental hormones.

Parturition begins when the balance shifts from progesterone-dominated quiescence to activation: maturation of the fetal HPA axis and rising placental CRH, a functional progesterone withdrawal, estrogen-induced oxytocin receptors and gap junctions, and prostaglandins that ripen the cervix and stimulate contractions. Cervical stretch triggers oxytocin release (Ferguson reflex, positive feedback). Labour has three stages: (1) onset to full cervical dilatation (10 cm), (2) full dilatation to birth of the baby, (3) delivery of the placenta and membranes.

Lactation: during pregnancy estrogen, progesterone, prolactin and hPL develop the breast, but high progesterone blocks copious milk production. Delivery of the placenta removes this block, and milk "comes in" ≈2–4 days postpartum. Suckling maintains it through two reflexes: prolactin release (milk synthesis) and oxytocin release (milk ejection by myoepithelial cells).

Erection (parasympathetic, S2–S4 via pelvic splanchnic and cavernous nerves): nerve terminals and endothelium release nitric oxide, which activates guanylyl cyclase in smooth muscle; cGMP lowers intracellular Ca²⁺ and relaxes the helicine arteries and trabecular smooth muscle. Blood fills the cavernous sinusoids of the corpora cavernosa, which compress the subtunical venules against the inelastic tunica albuginea (veno-occlusion), making the penis rigid. PDE5 degrades cGMP and ends erection; PDE5 inhibitors (sildenafil, tadalafil) prolong it. Emission (sympathetic, T12–L2 via the hypogastric nerves): smooth muscle of the epididymis, ductus deferens, seminal vesicles and prostate contracts, moving semen into the prostatic urethra, while the internal urethral sphincter at the bladder neck closes to prevent retrograde ejaculation. Ejaculation (somatic, pudendal nerve S2–S4): rhythmic contraction of bulbospongiosus and the pelvic floor expels semen. Mnemonic: Point (parasympathetic), Squeeze (sympathetic) and Shoot (somatic). The female sexual response uses the same NO–cGMP mechanism to engorge the clitoris and vestibular bulbs and produce vaginal transudation.

Combined hormonal contraception (pill, patch, ring: ethinylestradiol + progestogen) mainly suppresses ovulation by negative feedback on GnRH, FSH and LH (abolishing the LH surge), and also thickens cervical mucus and thins the endometrium. Progestogen-only methods: the traditional pill acts mainly on cervical mucus; desogestrel pills, the etonogestrel implant and medroxyprogesterone injection inhibit ovulation. The levonorgestrel intrauterine system thins the endometrium and thickens mucus. The copper IUD is toxic to sperm and ova and provokes a sterile inflammatory reaction; it is also the most effective emergency contraceptive. Oral emergency contraception (levonorgestrel, ulipristal acetate) works chiefly by delaying ovulation. Barrier methods (condoms) also protect against STIs. Sterilisation: vasectomy (division of the ductus deferens — not immediately effective; confirm azoospermia) and tubal occlusion or salpingectomy. The lactational amenorrhoea method relies on prolactin suppression of GnRH. Long-acting reversible methods (implant, IUD/IUS) have typical-use failure rates below 1 % per year.

Implantation outside the uterine cavity, ≈1–2 % of pregnancies; >95 % are tubal, most in the ampulla (≈70 %), then isthmus, fimbria and interstitial (cornual) segment. Risk factors: previous ectopic, pelvic inflammatory disease (Chlamydia), tubal surgery or sterilisation, IVF, smoking, conception with an IUD in situ. Typical presentation at 6–8 weeks: amenorrhoea, lower abdominal pain, vaginal bleeding; rupture causes haemoperitoneum, shoulder-tip pain (diaphragmatic irritation, C3–C5), collapse. Diagnosis by transvaginal ultrasound and serial β-hCG (suboptimal rise; no intrauterine sac above the discriminatory zone). Management: expectant, methotrexate, or laparoscopic salpingectomy/salpingotomy; anti-D if RhD negative.

Endometrial-like glands and stroma outside the uterus, affecting ≈10 % of women of reproductive age. Common sites: ovaries (endometrioma — "chocolate cyst"), uterosacral ligaments, rectouterine pouch, pelvic peritoneum; rarely bowel, bladder, scars, diaphragm. Theories: retrograde menstruation (Sampson), coelomic metaplasia, lymphatic/vascular spread. The lesions respond to cyclical hormones, bleed and cause inflammation and adhesions: dysmenorrhoea, deep dyspareunia, chronic pelvic pain, dyschezia, subfertility; fixed retroverted uterus and nodular uterosacral ligaments on examination. Diagnosis by imaging and laparoscopy; treatment with analgesia, hormonal suppression (COCP, progestogens, GnRH analogues) or surgical excision. Adenomyosis is the related condition of endometrium within the myometrium.

The commonest endocrine disorder of reproductive-age women (≈10 %). Diagnosis (Rotterdam criteria, refined in the 2023 international guideline) requires two of three after excluding other causes: (1) oligo-/anovulation, (2) clinical or biochemical hyperandrogenism (hirsutism, acne, raised free testosterone), (3) polycystic ovarian morphology on ultrasound (≥20 follicles per ovary) or raised AMH (not used in adolescents). Pathophysiology: rapid GnRH pulses with high LH driving theca androgens, and insulin resistance with hyperinsulinaemia that amplifies androgen production and lowers SHBG. Consequences: infertility, type 2 diabetes, dyslipidaemia, sleep apnoea, depression and — from chronic anovulation with unopposed estrogen — endometrial hyperplasia and carcinoma. Management: lifestyle and weight loss, COCP for cycle control and androgen symptoms, metformin, letrozole for ovulation induction.

Benign, estrogen- and progesterone-dependent tumours of myometrial smooth muscle — the commonest pelvic tumour in women (present in up to ≈70–80 % by age 50; more common and earlier in women of African ancestry). Classified as submucosal (distort the cavity: heavy bleeding, subfertility, miscarriage), intramural and subserosal/pedunculated. Symptoms: heavy menstrual bleeding with iron-deficiency anaemia, pelvic pressure, urinary frequency, constipation, subfertility; many are asymptomatic. They grow in pregnancy (red degeneration: acute pain) and shrink after menopause. Malignant transformation to leiomyosarcoma is very rare. Treatment: tranexamic acid, LNG-IUS, GnRH analogues/antagonists, uterine artery embolisation, myomectomy or hysterectomy.

Almost all cervical cancers are caused by persistent infection with high-risk HPV, especially types 16 and 18 (≈70 %). The viral oncoproteins E6 (degrades p53) and E7 (inactivates Rb) drive dysplasia — cervical intraepithelial neoplasia (CIN 1–3) — in the transformation zone, where metaplastic squamous cells are vulnerable. ≈70–80 % are squamous-cell carcinomas, most of the rest adenocarcinomas. Risk factors: early sexual debut, multiple partners, smoking, immunosuppression (HIV), long-term COCP use. Symptoms: post-coital, intermenstrual or postmenopausal bleeding and discharge; late disease causes ureteric obstruction (hydronephrosis, renal failure) and pelvic pain. Prevention: HPV vaccination (ideally before sexual activity) and screening by HPV testing with cytology triage, colposcopy and excision (LLETZ) of high-grade lesions. Spread is local (parametrium, vagina, bladder, rectum) and to pelvic lymph nodes.

The commonest cancer in women worldwide (lifetime risk ≈1 in 7–8 in high-income countries); ≈1 % of cases occur in men. Risk factors: age, female sex, prolonged estrogen exposure (early menarche, late menopause, nulliparity, late first pregnancy, HRT, obesity), family history and BRCA1/BRCA2 mutations, prior chest irradiation. Most arise in the terminal duct lobular unit; invasive carcinoma of no special type (ductal) is commonest, followed by lobular. About half arise in the upper outer quadrant (most glandular tissue). Signs: a hard, irregular, painless lump; skin dimpling and nipple retraction (tethering of suspensory (Cooper) ligaments and ducts); peau d'orange (dermal lymphatic obstruction); nipple discharge or Paget disease of the nipple; axillary nodes. Triple assessment (examination, imaging, core biopsy); receptor status (ER, PR, HER2) guides therapy (endocrine therapy, trastuzumab, chemotherapy); sentinel lymph node biopsy stages the axilla, the main lymphatic drainage route.

Twisting of the spermatic cord that obstructs venous then arterial flow to the testis — a urological emergency. Commonest in adolescents (peak 12–18 years) and neonates; predisposed by the bell-clapper deformity (tunica vaginalis attaches high on the cord, so the testis hangs freely). Presents with sudden severe unilateral scrotal pain, often with nausea and vomiting and lower abdominal pain (visceral afferents T10–L1); the testis is high-riding, horizontal and very tender, and the cremasteric reflex is usually absent. Salvage is ≈90–100 % if detorsion occurs within 6 hours and falls steeply thereafter, so suspected torsion goes straight to surgical exploration without delaying for imaging; both testes are fixed (bilateral orchidopexy). Differentials: torsion of the appendix testis ("blue dot sign"), epididymo-orchitis, trauma, hernia.

Cryptorchidism (undescended testis) affects ≈2–4 % of term and up to ≈30 % of preterm boys; most descend spontaneously by 3–6 months. Testes are usually in the inguinal canal (palpable) and should be brought down by orchidopexy at 6–18 months. Complications: impaired spermatogenesis (higher temperature), increased risk of testicular germ-cell tumour (seminoma), torsion and associated inguinal hernia (patent processus vaginalis). A retractile testis (active cremaster reflex) is a normal variant. Varicocele is dilatation of the pampiniform venous plexus ("bag of worms"), present in ≈15 % of men and ≈35–40 % of men with primary infertility, ≈90 % on the left — because the left testicular vein is longer, enters the left renal vein at a right angle, may lack valves and can be compressed between the aorta and superior mesenteric artery (nutcracker). It enlarges on standing and Valsalva and decompresses lying down. A sudden-onset or non-decompressing varicocele, especially on the right, suggests venous obstruction by a retroperitoneal mass (e.g. renal cell carcinoma).

BPH: nodular hyperplasia of glandular and stromal tissue in the transition zone around the prostatic urethra, driven by DHT; present in most men over 70. It compresses the urethra causing lower urinary tract symptoms — hesitancy, weak stream, terminal dribbling, incomplete emptying, frequency, nocturia, urgency — and can cause acute urinary retention, bladder trabeculation, stones and hydronephrosis. DRE: smooth, symmetrically enlarged, rubbery gland. It is not premalignant. Treatment: α1-blockers (tamsulosin — relax prostatic smooth muscle), 5α-reductase inhibitors (finasteride — shrink the gland, halve PSA), TURP. Prostate cancer: adenocarcinoma, the commonest cancer in men in many countries; ≈70 % arise in the peripheral zone, so they may be felt as a hard, irregular nodule on DRE and often cause no early urinary symptoms. Diagnosis: PSA, multiparametric MRI and targeted biopsy, graded by Gleason score/ISUP grade group. Spreads to pelvic and para-aortic nodes and to bone (osteoblastic/sclerotic metastases, especially lumbar spine and pelvis, via the prostatic and vertebral venous plexuses). Treatment ranges from active surveillance to radical prostatectomy, radiotherapy and androgen deprivation.

Failure to conceive after 12 months of regular unprotected intercourse (6 months if the woman is ≥35); affects ≈1 in 6 people of reproductive age. Causes are shared between partners: male factor (≈30–40 % contributory — abnormal semen from varicocele, hypogonadism, genetic causes such as Klinefelter syndrome and Y-chromosome microdeletions, obstruction including congenital absence of the vas in cystic fibrosis, drugs, anabolic steroids), ovulatory disorders (PCOS — the commonest; hypothalamic amenorrhoea; hyperprolactinaemia; premature ovarian insufficiency), tubal/peritoneal factors (PID, endometriosis, adhesions), uterine factors (fibroids, polyps, septum, Asherman syndrome), and unexplained (≈25 %). Basic work-up: semen analysis, mid-luteal progesterone, AMH/antral follicle count, tubal patency testing, and screening for rubella immunity and chlamydia. Treatments: ovulation induction, surgery, intrauterine insemination, IVF and ICSI.

Chlamydia trachomatis (the commonest bacterial STI): often asymptomatic; urethritis, cervicitis, epididymitis, pelvic inflammatory disease with tubal scarring → infertility, ectopic pregnancy and chronic pain; perihepatitis (Fitz-Hugh–Curtis); neonatal conjunctivitis and pneumonia. Neisseria gonorrhoeae: purulent urethral discharge, cervicitis, PID, disseminated infection (arthritis, pustules); rising antimicrobial resistance — ceftriaxone is first line. Syphilis (Treponema pallidum): painless chancre (primary), rash including palms and soles and condylomata lata (secondary), gummas and cardiovascular/neurosyphilis (tertiary); congenital syphilis — hence antenatal screening. Genital herpes (HSV-2 and HSV-1): painful vesicles and ulcers, recurrent; neonatal herpes risk at delivery. HPV: anogenital warts (types 6 and 11) and cancers (16, 18). Trichomonas vaginalis: frothy yellow-green discharge, "strawberry cervix". HIV, hepatitis B and mycoplasma genitalium are also sexually transmitted. Principles: test for co-infections, partner notification, condoms, vaccination (HPV, hepatitis B) and HIV pre-exposure prophylaxis.